Cedars-sinai Medical Center

Shlomo Melmed

Lin Pei

Xun Zhang

Gregory A Horwitz

Anthony P Heaney

Christoph J Auernhammer

Michael DeWitt Culler

Carol W Readhead

Toni Rita Prezant

Hidenori Fukuoka

Kolja Wawrowsky

Diane Prager

Yunguang Tong

Zhiyong Wang

Anat Ben-Shlomo

Sadanori Akita

Ilan Shimon

Ning-Ai Liu

The invention relates to methods and kits for the treatment of, prevention of, and lowering the chances of developing Cushing's Disease and/or hypercortisolism by the administration of a tyrosine kinase inhibitor, such as gefitinib.

Methods for treatment of Cushing'S disease and hypercortisolism using gefitinib

The instrumentation and methods described herein are based on imaging and measuring single cell dose response by fluorescent ion imaging that records live cell responses to drug doses. Dose response curves and other pharmacological parameters can be computed by imaging and measuring oscillation changes for each drug dose and each cell. The instrumentation and methods described herein provide a means of measuring statistical variability of cell populations for improved screening and development methods for drugs.

Method for drug screening and characterization by calcium flux

The present invention relates to the use of pituitary tumor transforming gene 1 (PTTG1) as a biomarker for diagnosing cancer as well as for determining cancer treatment responsiveness. In one embodiment, the present invention provides a method of treating cancer by inhibiting the expression of PTTG1, and administering a therapeutically effective amount of Aurora kinase inhibitor, HDAC inhibitor and/or ROS-generating agent.

PTTG1 as a biomarker for cancer treatment

Described are cells transfected with expression vectors containing pituitary tumor transfer gene (PTTG) and uses therefor. The PTTG nucleic acids may be operatively linked to a vector, optionally provided with control and expression sequences, and/or may be carried by a host cell. The host cell may be a thyroid stimulating hormone (TSH)-sensitive cell transfected with an expression vector comprising a DNA segment encoding functional PTTG, wherein the cell overexpresses PTTG in response to TSH. Also described is an in vitro cell model used to study biological processes mediated by PTTG and a method for evaluating a compound for its ability to modulate PTTG expression.

Transgenic cells transfected with pituitary tumor transforming gene (PTTG)) expression vectors and uses therefor

Disclosed is a transgenic vertebrate cell containing a nucleic acid construct comprising a murine SOCS-3 promoter, or an operative fragment thereof, or an operative derivative of either of these.

Transgenic expression from a SOCS-3 promoter in vertebrate cells

Disclosed are isolated antibodies that specifically bind a murine pituitary tumor transforming gene carboxy-terminal (PTTG-C) peptide. The inventive antibodies are useful in assays to determine levels of PTTG proteins or PTTG-C peptides present in a given sample (e.g., tissue samples, biological fluids, Western blots). The antibodies can also be used to purify PTTG proteins or PTTG-C peptides from crude cell extracts and the like. The antibodies are also considered therapeutically useful to counteract and/or supplement the biological effect of PTTG proteins in vivo.

Antibodies against mouse pituitary tumor transforming gene carboxy-terminal (PTTG-C) peptides

Disclosed is a method of inhibiting neoplastic cellular proliferation and/or transformation of mammalian breast or ovarian cells, including cells of human origin, in vitro or in vivo. The inventive method involves the use of a pituitary tumor transforming gene (PTTG)2 peptide, which has the ability to regulate endogenous PTTG1 expression and/or function in a dominant negative manner. In some embodiments, the invention is directed to gene-based treatments that deliver PTTG2-encoding polynucleotides to mammalian cells, whether in vitro or in vivo, to inhibit the endogenous expression of PTTG1. Other embodiments are directed to peptide-based treatments that deliver PTTG2 peptide molecules to the cells, which inhibit endogenous PTTG1 expression and/or PTTG1 function. Kits useful in practicing the inventive method are also disclosed.

Method of regulating biological activity of pituitary tumor transforming gene (PTTG)1 using PTTG2

Polypeptides are expressed by the pituitary-tumor-transforming-gene (PTTG), formerly known as pituitary-tumor-specific-gene (PTTG), and nucleic acids encode them. Examples are the human and rat PTTG proteins. The nucleic acids may be applied to the production of a recombinant protein, and to the detection of the presence of PTTG genes in different species. The nucleic acids may be operatively linked to a vector, optionally provided with control and expression sequences and/or being carried by a host cell. The nucleic acids may also be delivered to a mammal to compensate for the absence, or a defective expression, of endogenous protein. The nucleic acids, proteins, and antibodies are also employed in disgnostic assays, as well as, for example, in the production of anti-PTTG antibodies (protein), therapeutic compositions and other applications of the proteins and antibodies. Various kits utilize nucleic acids, polypeptides, and/or antibodies. A transgenic non-human mammal expresses PTTG.

Rat PTTG polypeptide and method for producing it

Disclosed is a null mutant (or knockout) rodent comprising in its germ cells an artificially induced PTTG null mutation. In some embodiments, the null mutant rodent can be generated by way of homologous recombination in an embryonic stem cell or germ cell. The inventive null mutant rodent can be used to study mammalian physiology at the cellular, tissue, and/or organismal level with respect to various phenotypes, including hyperglycemia, hypoinsulinaemia, hypoleptinemia, diabetes, chromosomal aneuploidy, premature centromere division, chromosomal damage, aberrant mitotic cellular division, thrombocytopenia, thymic hyperplasia, splenic hypoplasia, testicular hypoplasia, and female subfertility. Also disclosed is an animal model for diabetes. Also disclosed is a somatic or germ cell obtained from the null mutant rodent. Also disclosed is a cell line derived from a cell obtained from the null mutant rodent.

PTTG knockout rodent as a model to study mechanisms for various physiological phenomena, including diabetes

Polypeptides are expressed by the pituitary-tumor-transforming-gene (PTTG), formerly known as pituitary-tumor-specific-gene (PTSG), and nucleic acids encode them. Examples are the human and rat PTTG proteins. The nucleic acids may be applied to the production of a recombinant protein, and to the detection of the presence of PTTG genes in different species. The nucleic acids may be operatively linked to a vector, optionally provided with control and expression sequences and/or being carried by a host cell. The nucleic acids may also be delivered to a mammal to compensate for the absence, or a defective expression, of endogenous protein. The nucleic acids, proteins, and antibodies are also employed in disgnostic assays, as well as, for example, in the production of anti-PTTG antibodies (protein), therapeutic compositions and other applications of the proteins and antibodies. Various kits utilize nucleic acids, polypeptides, and/or antibodies. A transgenic non-human mammal expresses PTTG.

Human PTTG polypeptide and method for producing it

Disclosed is a method of inhibiting neoplastic cellular proliferation and/or transformation of mammalian cells, including cells of human origin, in vitro or in vivo. The inventive method involves the use of a pituitary tumor transforming gene carboxy-terminal peptide (PTTG-C), which has the ability to regulate endogenous pituitary, tumor transforming gene (PTTG) expression and/or function in a dominant negative manner. In some embodiments, the invention is directed to gene-based treatments that deliver PTTG-C-related polynucleotides to mammalian cells, whether in vitro or in vivo, to inhibit the endogenous expression of PTTG. Other embodiments are directed to peptide-based treatments that deliver PTTG-C peptide molecules to the cells, which inhibit endogenous PTTG expression and/or PTTG function. Additional embodiments directed to a method of inhibiting tumor angiogenesis, in vivo, are also disclosed. Also disclosed are compositions useful for inhibiting neoplastic cellular proliferation and/or transformation and tumor angiogenesis, including compositions comprising a PTTG carboxy-terminal peptide or comprising a chimeric or fusion protein that contains a first PTTG carboxy-terminal peptide segment and a second cellular uptake-enhancing and/or importation-competent peptide segment. Also disclosed are compositions comprising a PTTG carboxy-terminal-related polynucleotide, including compositions comprising expression vectors containing the PTTG-C-related polynucleotides. Kits comprising the inventive compositions are also disclosed for the treatment of neoplastic cellular proliferation in vitro or in vivo. Isolated PTTG-C peptides and PTTG-C-related polynucleotides are also disclosed, as are anti-PTTG-C-specific antibodies.

Pituitary tumor transforming gene (PTTG) carboxy-terminal peptides and methods of use thereof to inhibit neoplastic cellular proliferation and/or transformation

Disclosed is a method of inhibiting neoplastic cellular proliferation and/or transformation of mammalian cells, including cells of human origin, in vitro or in vivo. The inventive method involves the use of a composition containing a pituitary tumor transforming gene carboxy-terminal peptide (PTTG-C), which can be comprised in a chimeric protein, which has the ability to regulate endogenous pituitary tumor transforming gene (PTTG) expression and/or function in a dominant negative manner. Kits comprising the inventive compositions are also disclosed for the treatment of neoplastic cellular proliferation in vitro or in vivo. Isolated PTTG-C peptides and PTTG-C-containing chimeric proteins are described.

Disclosed are isolated antibodies that specifically bind a rat pituitary tumor transforming gene carboxy-terminal peptide (PTTG-C). These antibodies are believed to be particularly useful in connection with methods for inhibiting the neoplastic cellular proliferation and/or transformation of mammalian cells, including cells of human origin, whether in vivo or in vitro. This is based on the discovery that PTTG-C molecules have the ability to downregulate pituitary tumor transforming gene (PTTG) expression and/or PTTG function in a dominant negative manner.

Antibodies against rat pituitary tumor transforming gene carboxy-terminal (PTTG-C) peptides

Compositions and method for determining the presence of human PTTG peptide in a sample

Polypeptides are expressed by the pituitary-tumor-transforming-gene (PTTG), formerly known as pituitary-tumor-specific-gene (PTSG), and nucleic acids encode them. Examples are the human and rat PTTG proteins. The nucleic acids may be applied to the production of a recombinant protein, and to the detection of the presence of PTTG genes in different species. The nucleic acids may be operatively linked to a vector, optionally provided with control and expression sequences and/or being carried by a host cell. The nucleic acids may also be delivered to a mammal to compensate for the absence, or a defective expression, of endogenous protein. The nucleic acids, proteins, and antibodies are also employed in diagnostic assays, as well as, for example, in the production of anti-PTTG antibodies (protein), therapeutic compositions and other applications of the proteins and antibodies. Various kits utilize nucleic acids, polypeptides, and/or antibodies. A transgenic non-human mammal expresses PTTG.

Growing community of inventors

Los Angeles, CA, United States of America

Shlomo Melmed